STAT3 variants as a rheostat of immune tolerance

项目摘要/摘要(总体) 免疫系统的失调可能会对健康和福祉造成严重后果。尽管这是 通常情况下，这是一个复杂的过程，人类遗传学的最新进展使单基因的鉴定成为可能 与免疫失调密切相关的变异。在这里，在这个项目中，授予三个 互补的团队将共同努力，进一步揭示杂合突变是如何导致收益的 STAT3基因的功能活性缺失(GOF)与疾病的易感性很强。此外，通过我们的努力， 我们希望找到潜在的新方法来扭转这一缺陷。这项计划项目将有三个高度 由梅根·库珀博士、马克·安德森博士和亚历克斯·马森博士领导的协作和互动项目 以及两个科学核心。资助金的主要主题是： 1.更精细地分析STAT3 GOF患者的免疫细胞功能障碍 2.使用最先进的动物建模方法询问触发过程中的STAT3 GOF突变 皮肤炎与1型糖尿病 3.利用CRISPR/CAS9最先进的方法询问STAT3 GOF功能障碍 4.人类细胞STAT3基因缺陷修复的建模方法 这项工作的长期目标是提高我们对STAT3如何充当可调项的理解 控制免疫耐受和免疫失调的变阻器。这些研究的结果将有助于进一步 加深对自身免疫性炎症的认识，帮助改进自身免疫性炎症的治疗和治疗方法 诊断。

Project Summary/Abstract (Overall) Dysregulation of the immune system can have severe consequences on health and wellbeing. Although this is often a complex process, recent progress in human genetics has allowed for the identification of single gene variants that are strongly associated with immune dysregulation. Here, in this program project grant three complementary teams will be working together to further unravel how heterozygous mutations that lead to gain of function activity (GOF) of the STAT3 gene can strongly predispose to disease. Moreover, through our efforts we hope to discover potential new methods to reverse this defect. This program project will have three highly collaborative and interactive projects headed by Drs. Megan Cooper, Mark Anderson, and Alex Marson along with two scientific cores. The major themes of the grant are: 1. More refined analysis of the immune cell dysfunction in STAT3 GOF patients 2. Using state of the art animal modeling approaches to interrogate STAT3 GOF mutations in triggering skin inflammation and type 1 diabetes 3. Utilizing state of the art CRISPR/Cas9 methods to interrogate STAT3 GOF dysfunction 4. Modeling methods to genetically repair defective STAT3 in human cells The long-term objectives of this work are to improve our understanding of how STAT3 can serve as a tunable rheostat to control immune tolerance and immune dysregulation. Results of these studies will help further refine our understanding of autoimmunity inflammation and help improve methods for its treatment and diagnosis.